There is almost universal recognition that proteins help define biological systems particularly by influencing cell shape, structure and function. Proteins are generally made by steps that include transcription, translation, trafficking, and for some proteins, secretion or membrane targeting. The ability of the proteins to exist is impacted by degradative processes. See generally, Alberts, Be. et al. (1989) in Molecular Biology of the Cell (2nd ed.) Garland Publishing, Inc. New York and London; and Stryer, L. (1988) in Biochemistry W.H. Freeman and Co. New York.
Accordingly, nearly all biological systems have evolved several steps (pathways) that collectectively make proteins and then degrade them as needed. The combination of these steps, when focussed on a particular protein or group of proteins, is thought to govern the expression of that protein.
There have been many efforts to modulate protein expression particularly with respect to proteins known or suspected of being involved in mammalian disorders.
For example, one approach has been to identify compounds that can modulate the expression of a particular protein. Following this strategy, a compound can be administered to a primate and especially a human subject to alter at least one synthetic or degradative step to treat a medical condition. This strategy has been used to implement many successful therapies. See generally The Pharmacological Basis of Therapeutics (8th ed.) Gilman, A. et al. (eds.) McGraw-Hill Professionals Division, pp. 1264-1276, (1993).
For certain medical conditions, there have been reports that compounds with capacity to modulate protein expression can be used to treat the conditions even if those proteins are damaged.
There have been efforts to treat cystic fibrosis (CF) along these lines.
Briefly, there is understanding that mutations in the cystic fibrosis transmembrane regulator (CFTR) protein can lead to life-threatening illness. One CFTR mutation termed “ΔF508” is a common CFTR mutation. When functioning normally, CFTR is thought to be a necessary cAMP-activated chloride channel. In CF, this channel is thought to be misprocessed and retained in the endoplasmic reticulum of epithelial cells. See e.g., Lukacs et al., Gastroenterology, 109:282-284 (1995); Li et al., Nat. Genet., 3:311-316 (1993); and Cheng et al., Am. J. Physiol, 268:L615-L624 (1995).
There have been reports that growth of certain cells carrying the CF defect can grow better at reduced temperature or with compounds that alleviate trafficking defects in vitro. See e.g., Egan et al., Am. J. Physiol. 271:635-638 (1996); Brown et al., J. Clin. Invest., 99:1432-1444 (1997) and Sato et al., J. Biol. Chem., 271:635-638 (1996).
More generally, steps associated with protein trafficking and especially protein degradation have been disclosed. Some of these steps appear to implement various heat shock protein and/or ubiquitin-associated pathways. See e.g., Gething et al., Nature, 355:33-45 (1992) and Chiang et al., Science, 246:382-385 (1989)
It has been reported that 4-phenylbutyric acid (sometimes referred to as 4-PBA or Buphenyl), can be used to treat various medical conditions including CF. This compound has been approved for the treatment of certain urea cycle disorders. There has been some discussion that this compound may also find use in the treatment of certain hemoglobinopathies, including sickle cell disease, thalassemias; as well as cancer.
With respect to CF, there have been reports that 4-BPA can restore CFTR-mediated chloride transport. Clinical trials using this compound have provided encouraging results. See Rubenstein, R. C. et al. (1997) J. Clin. Invest. 100: 2457-2465; Rubenstein, R. C. (1998) Am. J. Respir. Crit. Care Med. 157: 484-490.
Other strategies have been implemented to modulate protein expression. One approach has been to identify compounds that alter the transcription of nucleic acids encoding a protein of interest.
For example, it has been disclosed that 4-PBA can enhance fetal hemoglobin levels by transcriptional “up” regulation. The effective has been reported to involve histone deacetylase. See e.g., Stamatoyannopoulos et al., Blood, 84:3198-3204 (1994); Lea et al., Anticancer Res., 15:879-883 (1995).
Accordingly, it would be desirable to have additional compounds and methods for modulating protein expression. It would be especially desirable to have carbocyclic aryl alkenoic acid derivatives and methods for using same that can be used to treat or prevent conditions or diseases impacted by undesired protein expression.